3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis.

Abstract

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18-1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4',6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.

• Authors: Oxana Kazakova, Codruța Șoica, Marat Babaev, Anastasiya Petrova, Elmira Khusnutdinova, Alexander Poptsov, Ioana Macașoi, George Drăghici, Ștefana Avram, Lavinia Vlaia, Alexandra Mioc, Marius Mioc, Cristina Dehelean, Adrian Voicu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 19 (Oct 02 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34639035 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Biological Products
• Triterpenes
• ursane
• lupane

Topics

• Angiogenesis Inhibitors
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Biological Products (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Models, Molecular
• Molecular Conformation
• Molecular Structure
• Protein Binding
• Structure-Activity Relationship
• Triterpenes (chemistry, pharmacology)